Method for purifying simvastatin

ABSTRACT

The present invention relates to a purification method of simvastatin crystal, more particularly to a method of effectively removing impurities contained in crude simvastatin obtained by a conventional synthetic method of simvastatin while minimizing loss of effective components to obtain high-quality simvastatin with good yield.

TECHNICAL FIELD

The present invention relates to a purification method of simvastatincrystal, more particularly to a method of effectively removingimpurities contained in crude simvastatin obtained by using aconventional synthetic method of simvastatin while minimizing loss ofeffective components to obtain high-quality simvastatin with good yield.

BACKGROUND ART

Simvastatin, a substance represented by the following Chemical Formula1, is known to cure hyperlipidemia due to its superior inhibitoryactivity against HMG Co-A reductase.

Generally, simvastatin is synthesized by a series of reactionscomprising hydrolysis, lactonization, alcohol protection of the lactonering, acylation and deprotection, by using lovastatin as a startingmaterial. A variety of preparation methods with improvements in eachstep of the synthesis have been disclosed [U.S. Pat. No. 4,444,784;Korean Patent Publication No. 2000-15179].

As mentioned above, there have been known many methods for preparingsimvastatin, and the kinds and contents of impurities contained in crudesimvastatin are known to vary depending upon the preparation methodused. However, typical impurities contained in crude simvastatin aresubstances represented by the following Chemical Formulas 2a, 2b and 2c.

The impurity represented by Chemical Formula 2a is generated by openingof the lactone ring; the impurity represented by Chemical Formula 2b isa dimer generated by esterification of 3-hydroxylactone and free acid;and the impurity represented by Chemical Formula 2c isanhydrosimvastatin with the 3-hydroxy of 3-hydroxylactone filtered. Inparticular, the dimer represented by Chemical Formula 2b is known verydifficult to remove even by the most precise and sophisticatedrecrystallization.

Korean Patent No. 133,599 discloses a method of reducing content of thedimer represented by Chemical Formula 2b to a level below 0.2%. However,the above patent controls generation of the dimer during the process ofsimvastatin preparation, and it is totally different from the presentinvention, which separates and removes the dimer from crude simvastatin.Moreover, the above patent uses 1.2 to 1.5 equivalents of strong acidduring lactonization, and requires an additional step to neutralize thestrong acid after the reaction is completed. Considering the difficultyin handling of strong acid, environmental effect and complicatedness ofpreparation steps, the above patent is limited in applying it to massproduction of an industrial scale.

It may be effective to obtain simvastatin with high-purity by minimizingimpurities by controlling the method of simvastatin synthesis. However,in view of mass production of an industrial scale, it will be much moreeffective to obtain simvastatin with high-purity by separating andremoving impurities contained in crude simvastatin, irrespective of thesynthesis method being used.

Accordingly, an object of the present invention is to provide a methodof purifying simvastatin by effectively separating and removingimpurities contained in crude simvastatin.

DISCLOSURE OF INVENTION

The present invention relates to a method of purifying crudesimvastatin, which comprises:

(a) a step of concentrating crude simvastatin by dissolving in asolvent, adding simvastatin seed in said concentrate for partialcrystallization and adding hexane or cyclohexane to obtain Crystal #1;

(b) a step of suspending said Crystal #1 in alkyl acetate and addinghexane or cyclohexane to obtain Crystal #2; and

(c) a step of dissolving said Crystal #2 in a solvent selected from agroup consisting of dimethoxyethane, tetrahydrofuran, 1,4-dioxane,dimethylether and dimethoxypropane and adding purified water to obtainpurified simvastatin crystal.

Hereinafter, the present invention is described in more detail.

The present invention relates to a method for obtaining high-puritysimvastatin crystal by effectively removing impurities contained incrude simvastatin obtained by a conventional synthetic method.

Any crude simvastatin obtained by a conventional synthetic method can beused in the present invention. In particular, the present inventionprovides an excellent method for removal of such impurities as the onegenerated by opening of the lactone ring (represented by ChemicalFormula 2a), a dimer represented by Chemical Formula 2b,anhydrosimvastatin represented by Chemical Formula 2c, and a mixture ofthese.

In a conventional preparation method of simvastatin, the impuritygenerated by opening of the lactone ring (represented by ChemicalFormula 2a) may be contained over 3.0%, and more precisely in the amountof 3.0 to 5.0%; the dimer represented by Chemical Formula 2b may becontained over 0.6%, and more precisely in the amount of 0.6 to 1.0%;and anhydrosimvastatin represented by Chemical Formula 2c may becontained over 1.0%, and more precisely in the amount of 1.0 to 2.0%.These impurities may be contained alone or in combination of two orthree components. Also, depending upon the preparation method,triphenylphosphine oxide may be contained as an impurity over 2%, andmore precisely in the amount of 2.0 to 3.0%, which can be alsoeffectively removed by the method of the present invention.

Each step of the present invention is described in greater detailhereunder.

The step of obtaining Crystal #1 is as follows. Crude simvastatin isdissolved in an organic solvent. This solution is concentrated at atemperature ranging from 0 to 40° C., more preferably at a temperatureof from 0 to 15° C. For the organic solvent, methylene chloride,chloroform, tetrahydrofuran, ethyl acetate, etc. may be used. Theconcentrated solution is seeded with a trace amount of simvastatin forpartial crystallization. Then, hexane or cyclohexane is added forcomplete crystallization. The crystallized solution is stirred at −10 to30° C. for from 30 minutes to 3 hours and filtered to obtain Crystal #1.

The step of obtaining the Crystal #1 is characterized by the seedingprocess. If the solution is directly filtered without seeding, thesolution should be heated to increase the filtering efficiency. However,the increase in temperature causes the increase in content of the dimerrepresented by Chemical Formula 2b. Also, with regard to addition of anonpolar solvent such as hexane or cyclohexane, filtering aftercrystallization becomes very difficult unless seeding is carried out.The Crystal #1 obtained by carrying out the seeding process according tothe present invention contains quite reduced amount of the impuritygenerated by opening of the lactone ring (represented by ChemicalFormula 2a). Also, the dimer represented by Chemical Formula 2b andanhydrosimvastatin represented by Chemical Formula 2c are removedsignificantly. Moreover, industrialization is made possible by resolvingthe problems of crystallization and filtration.

The next step of obtaining Crystal #2 is as follows. The Crystal #1 issuspended in alkyl acetate such as ethyl acetate, isopropyl acetate,butyl acetate or isobutyl acetate. Then, hexane or cyclohexane is addedand the temperature is maintained in the range of from 0 to 40° C. Ifthe temperature of the solution is below 0° C., filtration becomesinsufficient due to incomplete crystallization. In contrast, if itexceeds 40° C., the content of the dimer increases. Then, the solutionis left for from 30 minutes to 2 hours at 0 to 5° C. The solution isstirred for from 30 minutes to 4 hours in the same temperature range,and filtered to obtain Crystal #2.

This step of obtaining Crystal #2 significantly removestriphenylphosphine oxide. Also, the dimer represented by ChemicalFormula 2b and anhydrosimvastatin represented by Chemical Formula 2c areremoved significantly.

The last step of obtaining the final simvastatin crystal is as follows.The Crystal #2 is completely dissolved in a solvent, such asdimethoxyethane, tetrahydrofuran, 1,4-dioxane, dimethylether ordimethoxypropane. Then, active carbon is added to the solution, and thesolution is filtered at 15 to 30° C. for from 30 minutes to 2 hours,more preferably, at 20 to 25° C. for from 30 minutes to 1 hour whilestirring. The filtration process using active carbon is an optionalstep. By this process, color of simvastatin is improved, and impuritiesother than those mentioned above, such as some heavy metals, are removedeffectively. Purified water is slowly added to the filtrate at 10 to 30°C. for from 30 minutes to 3 hours. This solution is stirred at the sametemperature for from 1 to 3 hours and filtered to obtain purifiedsimvastatin.

The present invention is also characterized by selection of solventsthat dissolve and grow the crystal. Particularly, the present inventiondoest not use any alcoholic solvent. If an alcoholic solvent is used,other impurities such as alkyl ester may be generated. The presentinvention uses hexane or cyclohexane as a crystallization solvent forobtaining Crystal #1 and Crystal #2, and purified water for obtainingthe final crystal. These solvents prevent coagulation during the crystalgrowth and remove some water-soluble inorganic salts. Therefore, theyincrease efficiency and purity and readily industrialize thepurification process of simvastatin.

The final simvastatin crystal obtained by the present invention containsless than 0.1% of the impurity generated by opening of the lactone ring(represented by Chemical Formula 2a), less than 0.4% of the dimerrepresented by Chemical Formula 2b, and less than 0.4% ofanhydrosimvastatin represented by Chemical Formula 2c. Morespecifically, it contains from 0.05 to 0.1% of the impurity generated byopening of the lactone ring (represented by Chemical Formula 2a), from0.2 to 0.4% of the dimer represented by Chemical Formula 2b, and from0.1 to 0.4% of anhydrosimvastatin represented by Chemical Formula 2c.

Also, the present invention minimizes loss of simvastatin during thepurification. The purity of simvastatin crystal obtained by the presentinvention was over 99% and was significantly higher than that of crudesimvastatin.

Also, if the solution remaining after purification is collected and usedin the step of obtaining Crystal #1, the total yield can be improved byfrom 5 to 10%.

The present invention is explained in more detail based on the followingExamples but they should not be construed as limiting the scope of thisinvention.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a result of HPLC analysis for crude simvastatin used inExample 1.

FIG. 2 shows a result of HPLC analysis for Crystal #1 obtained inExample 1.

FIG. 3 shows a result of HPLC analysis for Crystal #2 obtained inExample 1.

FIG. 4 shows a result of HPLC analysis for the final simvastatin crystalobtained in Example 1.

EXAMPLE Example 1

10 g of crude simvastatin (purity: 91.28%) was dissolved in 650 ml ofmethylene chloride and completely concentrated at about 15° C. Duringthe concentration, simvastatin was added in as a seed forcrystallization. 3000 ml of hexane was added for 30 minutes whilevigorously stirring the solution. Then, the solution was slowly cooledto about 5° C. for 1 hour. At the same temperature (about 5° C.), thesolution was stirred for 1 hour, and then filtered. The filtrate waswashed with hexane and dried to obtain 93.3 g of Crystal #1.

The obtained 93.3g of Crystal #1 was suspended in 280 ml of ethylacetate. Then, 1400 ml of hexane was dropped for 30 minutes and thetemperature was raised to 30° C. The solution was cooled to 5° C. for 1hour, stirred at the same temperature for 1 hour, and then filtered. Thefiltration mother liquor was collected and dried. The crystal was washedwith hexane and dried to obtain 83.7 g of Crystal #2.

The obtained 83.7 g of Crystal #2 was dissolved in 350 ml ofdimethoxyethane. After adding 4.3 g of active carbon, the solution wasstirred at 20° C. for 30 minutes and filtered. The filtrate was washedwith 350 ml of dimethoxyethane and 1300 ml of water was dropped for 1hour at 20° C. After stirring for 1 hour at the same temperature, it waswashed with 1700 ml of water. Then, it was washed with 880 ml of hexaneand dried to obtain 82.0 g of high-purity simvastatin crystal (purity:99.32%).

Solutions remaining in the first, second and third purification stepswere collected and concentrated. This solution was placed under the samepurification process as shown above to further obtain 5 g of simvastatincrystal (purity: 99.13%).

Each crystal obtained in each crystallization step was analyzed with anHPLC (Waters; 2690). The content analysis result is shown in thefollowing Table 1. TABLE 1 Impurities Yield Chemical Chemical ChemicalBy Simvastatin Triphenylphosphine Formula Formula Formula weight ByClassification Weight Purity oxide 2a 2b 2c (g)^(a)) purity⁾ Crude  (100g) 91.28% 2.56% 3.33% 0.62% 1.46% — — simvastatin Crystal #1 93.3 g96.86% 1.55% 0.39% 0.52% 0.52% 93.3% 99.0% Crystal #2 83.7 g 99.15%0.20% 0.04% 0.39% 0.16% 89.0% 91.2% Simvastatin 82.0 g 99.32% 0.05%0.04% 0.38% 0.15% 98.0% 98.2%^(a))Yield of simvastatin obtained from 100 g of crude simvastatin.^(b))Yield calculated by considering purities of crude simvastatin andsimvastatin crystals.

As seen in Table 1, the total yield of the simvastatin crystal obtainedby the present invention was 82.0%, and the total yield calculated byconsidering the purity of crude simvastatin was 89.2%.

Example 2

100 g of crude simvastatin was dissolved in 650 ml of tetrahydrofuranand completely concentrated at about 15° C. During the concentration,simvastatin was added in as a seed for crystallization. 3000 ml ofdiethyl ether was added for 30 minutes while vigorously stirring thesolution at 15° C. Then, the solution was slowly cooled to 5° C. for 1hour. This solution was stirred for 1 hour at 5° C., and then filteredand dried to obtain 91g of Crystal #1.

The obtained 91 g of Crystal #1 was suspended in 350 ml of isopropylacetate. Then, 1400 ml of diethyl ether was dropped for 30 minutes andthe temperature was raised to 30° C. The solution was cooled to 5° C.for 1 hour, stirred at the same temperature for 1 hour, and thenfiltered. The filtration mother liquor was collected and dried. Thecrystal was washed with hexane and dried to obtain 77.35 g of Crystal#2.

The obtained 77.35 g of Crystal #2 was dissolved in 350 ml of1,4-dioxane. After adding 4.3 g of active carbon, the solution wasstirred at 20° C. for 30 minutes and filtered. The filtrate was washedwith 88 ml of 1,4-dioxane and 1300 ml of water was dropped for 1 hour at20° C. After stirring for 1 hour at the same temperature, it was washedwith 1700 ml of water. Then, it was washed with hexane and dried toobtain 75.0 g of high-purity simvastatin.

Each crystal obtained in each crystallization step was analyzed with anHPLC (Waters; 2690). The content analysis result is shown in thefollowing Table 2. TABLE 2 Impurities Yield Chemical Chemical ChemicalBy Simvastatin Triphenylphosphine Formula Formula Formula weight ByClassification Weight Purity oxide 2a 2b 2c (g)^(a)) purity⁾ Crude (100g) 91.28% 2.56% 3.33% 0.62% 1.46% — — simvastatin Crystal #1 91 g 96.21%1.48% 0.45% 0.59% 0.53% 91.0% 95.9% Crystal #2 77.35 g 99.01% 0.19%0.05% 0.35% 0.15% 85.0% 87.4% Simvastatin 75.0 g 99.12% 0.04% 0.04%0.34% 0.15% 97.0% 97.1%^(a))Yield of simvastatin obtained from 100 g of crude simvastatin.^(b))Yield calculated by considering purities of crude simvastatin andsimvastatin crystals.

As described above, the present invention effectively removes impuritiescontained in crude simvastatin obtained in the course of simvastatinsynthesis while minimizing the loss of acquired simvastatin, thus beinguseful for obtaining high-purity simvastatin.

While the present invention has been described in detail with referenceto the preferred embodiments, those skilled in the art will appreciatethat various modifications and substitutions can be made thereto withoutdeparting from the spirit and scope of the present invention as setforth in the appended claims.

1. A purification method of crude simvastatin comprising: (a) a step ofconcentrating crude simvastatin by dissolving in a solvent, addingsimvastatin seed in said concentrate for partial crystallization andadding hexane or cyclohexane to obtain Crystal #1; (b) a step ofsuspending said Crystal #1 in alkyl acetate and adding hexane orcyclohexane to obtain Crystal #2; and (c) a step of dissolving saidCrystal #2 in a solvent selected from a group consisting ofdimethoxyethane, tetrahydrofuran, 1,4dioxane, dimethylether anddimethoxypropane and adding purified water to obtain purifiedsimvastatin crystal.
 2. The purification method according to claim 1,wherein said crude simvastatin contains as impurities a compoundrepresented by the following Chemical Formula 2a,

which is generated by opening of the lactone ring, or a dimerrepresented by the following Chemical Formula 2b, or anhydrosimvastatinrepresented by the following Chemical Formula 2c or a mixture of thesethereof.
 3. The purification method according to claim 2, wherein saidcrude simvastatin contains as impurities more than 3% of the compoundrepresented by Chemical Formula 2a, which is generated by opening of thelactone ring, or more than 0.6% of the dimer represented by ChemicalFormula 2b, or more than 1% of anhydrosimvastatin represented byChemical Formula 2c or a mixture of these thereof.
 4. The purificationmethod according to any one of claims 1 to 3, wherein said crudesimvastatin further contains more than 2% of triphenylphosphine oxide asan impurity.
 5. The purification method according to claim 1, whereinsaid solvent dissolving said crude simvastatin is selected from a groupconsisting of methylene chloride, chloroform, tetrahydrofuran and ethylacetate.
 6. The purification method according to claim 1, wherein thetemperature of dissolving said crude simvastatin in step (a) ismaintained in the range of 0 to 40° C.
 7. The purification methodaccording to claim 1, wherein said temperature of suspending said crudesimvastatin in step (b) is maintained in the range of 0 to 40° C.
 8. Thepurification method according to claim 1, wherein said purified water at10 to 30° C. is added for 30 minutes −3 hours in step (c).
 9. Thepurification method according to claim 1, wherein a filtration processusing active carbon is carried out prior to adding purified water tosaid Crystal #2 in step (c).
 10. The purification method according toclaim 1, wherein solutions remaining from steps (a), (b) and (c) arecollected, concentrated and added to said crude simvastatin in said step(a).
 11. Simvastatin containing less than 0.1% of a compound representedby Chemical Formula 2a, which is generated by opening of the lactonering, less than 0.4% of a dimer represented by the following ChemicalFormula 2b, and less than 0.4% of anhydrosimvastatin represented by thefollowing Chemical Formula 2c as impurities.